Trinucleotide Repeat Disorders
Part 3: Polyglutamine Diseases

Descriptions of other diseases that involve codon repeat expansions.

SBMA (Spinobulbar Muscular Atrophy)

SBMA (Spinobulbar Muscular Atrophy) occurs predominantly in males and is characterized by weakness and atrophy of the proximal muscles. Difficulties with swallowing and articulating speech are also common symptoms of SBMA. As the first word of its name implies, the disease mainly affects the spinal cord (“spino-”) and a part of the brain called the bulbar region (“-bulbar”). (See Figure F-4.)

The Gene:

The gene involved in SBMA is called the Androgen Receptor (AR) gene. It is located on the X chromosome, which is one of the so-called sex chromosomes. (Unlike most of our chromosomes, the sex chromosomes differ between males and females and this is why SBMA occurs predominantly in males. To learn more about chromosomes, click here.) Typically, in asymptomatic individuals there are between 9 and 36 copies of CAG in the AR allele. In a person with the disease, however, the allele has anywhere between 38 and 62 copies. At present, not enough data exist to fully understand the effect that alleles with 37 copies of CAG will have on individuals.

The Protein:

Hearing the oft-repeated statement “DNA codes for proteins” might lead one to believe that it is as simple as show me DNA and poof!, you have a protein. Actually, the process is much more complex than that. In fact, the full sequence of events is broken up into several parts, one of which is called transcription. The Androgen Receptor gene codes for a protein of the same name, the Androgen Receptor (also abbreviated “AR”). Because the AR protein is a key player in transcription, it is aptly titled a transcription factor.

In its normal state, then, the AR protein helps cells carry out the instructions contained within DNA. (For more in-depth discussion of DNA and the genetic code, click here.) However, in people with SBMA, the protein has extra glutamines, resulting from the extra CAGs in the AR gene. Although scientists do not yet have a definitive explanation as to why the extra glutamines cause degeneration of the neuron, it seems likely that the extra glutamines create an altered form of the AR protein that does not perform its actions in the same way as the normal AR. This mechanism for degeneration of the neuron is much like the one for Huntington’s Disease, as illustrated in Figure A-3.

Another theory suggests that the degeneration of the nerve cell is a result of neuronal inclusions (NIs). This theory, too, has its equivalent in the study of Huntington’s Disease. (Click here for more about nerve cell death in HD). According to the theory, the extra glutamines in the protein have a way of attracting other proteins to group together with the AR. This aggregation of proteins causes clumps, or inclusions, which may be solely responsible for damage to the nerve cell. More research in this area is necessary to find out definitively if the NIs are the true cause of damage. (See Figure F-5.)

How the Symptoms Come About:

Whatever the mechanism, once the nerve cells become damaged, the symptoms of SBMA begin to appear. As mentioned above, one of the main areas of the body that SBMA affects is the spinal cord. More precisely, it affects the parts of the cord known as the anterior horn and the dorsal root ganglion. The dorsal root ganglion is a group of nerve cell bodies that pass sensory information to other spinal cord nerve cells and on to the brain for analysis. The anterior horn is a region of the spinal cord that contains cell bodies of motor neurons, which put the brain’s decisions (based on the sensory info) into action. These two regions of the spinal cord are thus essential for control of fine muscle movements. When the dorsal root ganglion is damaged, the brain cannot receive proper input and thus cannot plan a movement of the muscle. When the anterior horn is damaged, the brain’s planned movement cannot be carried out. Thus, if either of these regions is not functioning correctly, then the muscles are not able to carry out the same motions that they had always done before. This inability to perform normal motions is why muscle weakness and atrophy are so common in SBMA. (See Figure F-6.)

But the spinal cord is not the only body part affected by SBMA; the bulbar region of the brain is harmed as well. The bulbar region is composed of the cerebellum, the medulla and the pons. (For a tour of brain structures, including these three, click here.) An extension of the spinal cord at the base of the brain, the medulla and pons are responsible for some of the functions that keep us alive. Functions that we usually never think about, like breathing, blood circulation, and simple actions like swallowing are all in large part controlled by the medulla and pons. More complex functions, however, require use of the cerebellum. The cerebellum is where our learned movements are stored—it helps refine a great deal of motor activities, from throwing a baseball to speaking. Given the roles of the medulla, pons, and cerebellum, it’s no wonder why damage to these areas can cause difficulty swallowing and articulating speech, two more symptoms of SBMA. (See Figure F-7.)

Last Modified: 9-18-02

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